Vitamin A is an essential nutrient for healthy reproduction, vision, organ (re)generation, immune control and energy metabolism. Fortunately, our body very efficiently manages dietary uptake, storage and distribution of vitamin A to all tissues. By far the most vitamin A (>80%) is stored (as retinyl esters) in the liver, which also regulates controlled release to the bloodstream (as retinol) to distribute to vitamin A-demanding tissues. Even in the complete absence of vitamin A intake, a healthy liver can support normal circulating retinol levels for many months before vitamin A deficiency kicks in, which typically reveals itself in night blindness and uncontrolled infections. Patients with a chronic liver disease are believed to be at increased risk for developing vitamin A deficiency as their sick liver is unable to support efficient bile production for intestinal absorption of vitamin A. Moreover, the development of fibrosis leads to active release of vitamin A from the liver. However, there is still a lot of controversy about the effect of liver disease on vitamin A metabolism. In this thesis, we report a few remarkable observations that may change our view on the association between liver disease and vitamin A deficiency. First, we identified a novel enzyme, hormone-sensitive lipase (HSL), as an important factor that regulates vitamin A-release from the healthy liver. Secondly, we found that mice with a fibrotic fatty liver, a model for non-alcoholic fatty liver disease – NAFLD), actually stores more vitamin A in the liver than healthy controls, promoting retinyl ester formation and reducing retinol production. This leads to retinol deficiency, not vitamin A deficiency. Thirdly, patients with glycogen storage disease Ia (GSD Ia) also develop fatty liver, but while their liver vitamin A levels are normal, they have clearly increased serum retinol levels that may cause vitamin A-toxicity. Finally, we show that therapeutic bile acids that activate the Farnesoid X receptor (FXR) strongly affect vitamin A metabolism in the liver and reduce vitamin A storage. In conclusion, vitamin A metabolism is heavily disturbed in fatty liver disease, but does not lead to true vitamin A deficiency. Therapeutic bile acids may fix or aggravate this, which remains to be established in future studies. At least it seems clear that oral supplementation of vitamin A is unlikely to be of any therapeutic value for NAFLD patients.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2019|